The rarity of spinal muscle atrophy (SMA) means that promising new treatments can be tested in only a limited spectrum of patients for approval. Researchers evaluated a newly approved drug, asasnogene abeparvovec, in a wider range of patients to obtain comprehensive data on the profile of its side effects. They report in the Journal of Neuromuscular Diseases that the drug is associated with an immune response against the adeno-associated viral vector and requires careful control but has no long-term adverse effects.
In recent years, the availability of a growing number of drug treatments has significantly changed the course of SMA. One of these is onasemnogenic abeparvovec (Zolgensma®), an adeno-associated viral (AAV9) factor-based gene therapy that introduces a functional copy of the SMN1 gene in motor neurons by means of one intravenous injection.
SMA is referred to as an orphan disease because it affects only one in 6,000-10,000 newborns worldwide. SMA type 1 is good for about 60% of all cases. In the main clinical study based on the approval of monosaccharogenous abeparvovec, only 22 infants received this therapy. Twenty of them lived and breathed without a permanent ventilator after 14 months, when normally only a quarter of untreated patients would survive without the need for a ventilator. Based on these results, the FS Food and Drug Administration (FDA) approved the therapy for all types of SMA until the age of two years, and the European Medicine Agency (EMA) extended the label to all patients, or showed a phenotype of SMA . type 1 or with up to three SMN2 copies.
“SMA is a rare disease and important studies only included patients with SMA type 1 up to the age of eight months,” explained lead researcher Prof. Dr. Janbernd Kirschner, MD, Department of Neuropediatrics, Bonn University Hospital, Bonn, Germany. “However, the FDA and EMA have approved the treatment for a wider range of patients, which has resulted in discussions about how safe and effective the treatment is in elderly and pregnant patients and in those with SMA type 2.”
Researchers report their experience with eight consecutive SMA patients treated with the standard dose of onasemnogenic abeparvovec (1.1 × 1014 vg / kg) at University Hospital Bonn, Germany. All patients received prophylactic immunosuppression with prednisolone for four weeks starting on the day before gene therapy. The patients (four men, four women, age range 10-37 months) weighed between seven and 12 kilograms. All patients had two or three copies of the SMN2 gene and were previously treated with nuisances, also approved for treatment of SMA.
After treatment, all patients showed a temporary increase in body temperature and an increase in transaminase levels (transaminases are enzymes that are important in the synthesis of amino acids, which form proteins). In all but one patient, it was necessary to increase or decrease the standard steroid dose in order to control the immune response. In one serious case, liver damage was associated with limited liver function. This patient received steroid pulse therapy for five days after which he recovered completely. After therapy, six patients had asymptomatic thrombocytopenia (abnormally low platelets). Liver values and blood counts returned to normal and almost normal levels in the observation period after treatment. Four patients had an increase in troponin I levels, which may be a sign of heart failure, but heart evaluation showed no abnormalities.
“Our experience with eight patients older than eight months adds important findings to the growing body of evidence that treatment of SMA with non-anemnogenic abeparvovec is often associated with an immune response against the AAV vector,” notes Prof. Dr. Kirschner op. “This immune response mainly affects the liver and hematopoietic system and can be serious in some cases. However, it was possible to monitor the immune response in all patients by proactively monitoring and adjusting the steroid dose, and we have no long-term term-side- effects due to the immune response.
“It is premature to assess whether serious organ damage with long-term consequences can always be prevented. Further research is needed to better understand the immune response to gene therapy and ideally to identify patients at risk for a more severe response,” he concluded.
Spinal muscular atrophy (SMA) is a rare genetic neurodegenerative disease. It primarily affects spinal motor neurons and leads to progressive muscle weakness. The spectrum of severity ranges from severe cases beginning in the first six months of life (SMA type 1) to later onset in childhood or adolescence (SMA types 2-4). SMA is caused by mutations in the survival motor neurons. Without treatment, SMA type 1 is associated with death as the need for permanent ventilation within the first two years of life.
Friese, J., and others. (2021) Safety monitoring of gene therapy for spinal muscle atrophy with Onasemnogene Abeparvovec – A single center experience. Journal of Neuromuscular Diseases. doi.org/10.3233/JND-200593.